The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901.
A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide PD 0325901.
Barrett
Stephen D
SD
Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA.
Bridges
Alexander J
AJ
Dudley
David T
DT
Saltiel
Alan R
AR
Fergus
James H
JH
Flamme
Cathlin M
CM
Delaney
Amy M
AM
Kaufman
Michael
M
LePage
Sophie
S
Leopold
Wilbur R
WR
Przybranowski
Sally A
SA
Sebolt-Leopold
Judith
J
Van Becelaere
Keri
K
Doherty
Annette M
AM
Kennedy
Robert M
RM
Marston
Dan
D
Howard
W Allen
WA
Smith
Yvonne
Y
Warmus
Joseph S
JS
Tecle
Haile
H
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001565:Benzoates / Q000737:chemistry; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000737:chemistry; D020128:Inhibitory Concentration 50; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D051379:Mice; D009368:Neoplasm Transplantation; D012995:Solubility; D062367:ortho-Aminobenzoates / Q000737:chemistry
C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001549:Benzamides; D001565:Benzoates; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; C506614:mirdametinib; D004159:Diphenylamine; D048728:MAP Kinase Kinase Kinase 1